SatisfACtion: Phase I/II, Open-label, Multi-center Study of [225Ac]Ac-PSMA-R2 in Men With mHSPC and Heavily Pre-treated PSMA-positive mCRPC, With/Without Prior 177Lu-labelled PSMA-targeted Radioligand Therapy
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 33
- 试验地点
- 14
- 主要终点
- Incidence and severity of DLTs during the DLT observation period
研究概览
简要总结
The purpose of this study is to learn if the study drug, [225Ac]Ac-PSMA-R2, is safe and tolerable, and has anti-tumor activity in treated patients.
详细描述
First in human (FIH) phase I/II study of 225Ac-PSMA-R2 in PSMA-positive metastatic prostate cancer across three groups: post-177Lu mCRPC, pre-177Lu mCRPC, and 177Lu-naïve mHSPC, evaluating Q6W/Q4W dosing. Dose escalation will enroll ~18-22 participants per group/schedule to define MTD/RDE, guided by safety, tolerability, PK/dosimetry, and preliminary anti-tumor activity, with possible expansion based on benefit-risk.
Enrollment and dosing for all participants in Group 1, Group 2, and Group 3 have been completed. Further enrollment has been halted, and no additional dose escalation cohorts or Phase 2 dose expansion cohorts will be opened; enrollment in this study is now considered complete. The decision to halt enrolment was not driven by any safety concerns identified in the study to date, but rather by a lowered expectation of benefit. Accordingly, the study will not proceed to Phase 2, and a recommended Phase 2 dose was not established
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Evidence of PSMA-positive disease by 68Ga-PSMA-11 PET/CT and eligible as determined by central reading
- •Documented progressive mCRPC or mHSPC
- •Adequate organ function
- •Prior orchiectomy or ongoing ADT and should have received prior 177Lu-PSMA-RLT (Group1 dose escalation & expansion) or never received 177Lu-PSMA-RLT (Group 2 and Group 3 dose escalation & expansion).
排除标准
- •Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy
- •Any systemic anti-cancer therapy within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy
- •Uncontrolled pain or incompatibility that may result in participant's lack of ability to comply with imaging procedures
- •History of CNS metastases and symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
- •History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to ICF signature and/or clinically active significant cardiac disease
- •Diagnosis of other malignancies in the past three years expected to alter life expectancy or may interfere with disease assessment
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Group-1 (mCRPC/ post-177Lu)
- Dose Escalation: All eligible participants with Metastatic Castration Resistant Prostate Cancer (mCRPC) who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), post-taxane based chemotherapy and heavily pre-treated and having already received prior 177Lu-labelled Prostate Specific Membrane Antigen (PSMA)-targeting Radioligand Therapy (RLT) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 1.
- Dose Expansion: Once RDE is determined for Group 1, participants who have previously received 177Lu-PSMA-RLT will be enrolled in Group 1 dose expansion.
干预措施: 225Ac-PSMA-R2 (Drug)
Group-1 (mCRPC/ post-177Lu)
- Dose Escalation: All eligible participants with Metastatic Castration Resistant Prostate Cancer (mCRPC) who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), post-taxane based chemotherapy and heavily pre-treated and having already received prior 177Lu-labelled Prostate Specific Membrane Antigen (PSMA)-targeting Radioligand Therapy (RLT) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 1.
- Dose Expansion: Once RDE is determined for Group 1, participants who have previously received 177Lu-PSMA-RLT will be enrolled in Group 1 dose expansion.
干预措施: 68Ga-PSMA-R2 (Radiation)
Group-2 (mCRPC/ pre-177Lu)
- Dose Escalation: All eligible participants with mCRPC who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), prior taxane-based chemotherapy is not required, but have never been treated with 177Lu-labelled PSMA-targeted RLT (177Lu-labelled PSMA-targeted RLT treatment naïve) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 2.
- Dose Expansion: Once RDE is determined for Group 2, participants naïve to 177Lu-labelled PSMA-targeted Radioligand Therapy (RLT) will be enrolled in Group 2 dose expansion.
干预措施: 225Ac-PSMA-R2 (Drug)
Group-2 (mCRPC/ pre-177Lu)
- Dose Escalation: All eligible participants with mCRPC who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), prior taxane-based chemotherapy is not required, but have never been treated with 177Lu-labelled PSMA-targeted RLT (177Lu-labelled PSMA-targeted RLT treatment naïve) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 2.
- Dose Expansion: Once RDE is determined for Group 2, participants naïve to 177Lu-labelled PSMA-targeted Radioligand Therapy (RLT) will be enrolled in Group 2 dose expansion.
干预措施: 68Ga-PSMA-11 (Radiation)
Group 3 (mHSPC/ pre-177Lu)
- Dose Escalation: All eligible participants with mHSPC (177Lu-labelled PSMA-targeted RLT treatment naïve), who are treatment naive or minimally treated with a) luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) b) CYP17 inhibitor or ARDT exposure. Patient in this group will start treatment with 225Ac-PSMA-R2 after group 1 and group 2 patients.
- Dose Expansion: Once RDE is determined for Group 3, participants will be enrolled in Group 3 dose expansion.
干预措施: 225Ac-PSMA-R2 (Drug)
Group 3 (mHSPC/ pre-177Lu)
- Dose Escalation: All eligible participants with mHSPC (177Lu-labelled PSMA-targeted RLT treatment naïve), who are treatment naive or minimally treated with a) luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) b) CYP17 inhibitor or ARDT exposure. Patient in this group will start treatment with 225Ac-PSMA-R2 after group 1 and group 2 patients.
- Dose Expansion: Once RDE is determined for Group 3, participants will be enrolled in Group 3 dose expansion.
干预措施: 68Ga-PSMA-R2 (Radiation)
Group 3 (mHSPC/ pre-177Lu)
- Dose Escalation: All eligible participants with mHSPC (177Lu-labelled PSMA-targeted RLT treatment naïve), who are treatment naive or minimally treated with a) luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) b) CYP17 inhibitor or ARDT exposure. Patient in this group will start treatment with 225Ac-PSMA-R2 after group 1 and group 2 patients.
- Dose Expansion: Once RDE is determined for Group 3, participants will be enrolled in Group 3 dose expansion.
干预措施: 68Ga-PSMA-11 (Radiation)
Group-1 (mCRPC/ post-177Lu)
- Dose Escalation: All eligible participants with Metastatic Castration Resistant Prostate Cancer (mCRPC) who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), post-taxane based chemotherapy and heavily pre-treated and having already received prior 177Lu-labelled Prostate Specific Membrane Antigen (PSMA)-targeting Radioligand Therapy (RLT) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 1.
- Dose Expansion: Once RDE is determined for Group 1, participants who have previously received 177Lu-PSMA-RLT will be enrolled in Group 1 dose expansion.
干预措施: 68Ga-PSMA-11 (Radiation)
Group-2 (mCRPC/ pre-177Lu)
- Dose Escalation: All eligible participants with mCRPC who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), prior taxane-based chemotherapy is not required, but have never been treated with 177Lu-labelled PSMA-targeted RLT (177Lu-labelled PSMA-targeted RLT treatment naïve) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 2.
- Dose Expansion: Once RDE is determined for Group 2, participants naïve to 177Lu-labelled PSMA-targeted Radioligand Therapy (RLT) will be enrolled in Group 2 dose expansion.
干预措施: 68Ga-PSMA-R2 (Radiation)
结局指标
主要结局
Incidence and severity of DLTs during the DLT observation period
时间窗: Up to 6 weeks after the first 225Ac-PSMA-R2 dose administration
To determine the Recommended Dose for Expansion (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy in PSMA-positive in: * Group-1 (mCRPC): Participants previously treated with 177Lu-labelled PSMA-targeted RLT (post-177Lu). * Group-2 (mCRPC): Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu). * Group-3 (mHSPC): Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).
Dose Escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by group and frequency schedule
时间窗: From date of the first administration of 225Ac-PSMA-R2 till 30 days safety follow-up, assessed up to approximately 15 months
The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Dose Escalation: Tolerability
时间窗: Up to 6 weeks after the first 225AC-PSMA-R2 dose administration
Frequency of dose interruptions, reductions, discontinuations, and dose intensity by group.
Dose Expansion: Overall Response Rate (ORR)
时间窗: From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months
Overall Response Rate (ORR) is defined as the proportion of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) in soft tissue according to Prostate Cancer Working Group 3 (PCWG3) -modified RECIST v1.1 in absence of bone progression (as per PCWG3).
Phase I Dose Escalation: Tolerability
时间窗: Up to 6 weeks after the first 225AC-PSMA-R2 dose administration
Frequency of dose interruptions, reductions, discontinuations, and dose intensity by group.
Phase I Dose Escalation: Incidence and severity of DLTs during the DLT observation period
时间窗: Up to 6 weeks after the first 225Ac-PSMA-R2 dose administration
To determine the Recommended Dose for Expansion (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy in PSMA-positive in: * Group-1 (mCRPC): Participants previously treated with 177Lu-labelled PSMA-targeted RLT (post-177Lu). * Group-2 (mCRPC): Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu). * Group-3 (mHSPC): Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).
Phase I Dose Escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by group and frequency schedule
时间窗: From date of the first administration of 225Ac-PSMA-R2 till 30 days safety follow-up, assessed up to approximately 15 months
The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Phase ll Dose Expansion: Overall Response Rate (ORR)
时间窗: From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months
Overall Response Rate (ORR) is defined as the proportion of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) in soft tissue according to Prostate Cancer Working Group 3 (PCWG3) -modified RECIST v1.1 in absence of bone progression (as per PCWG3).
次要结局
- Dose Escalation: Incidence and severity of AEs and serious adverse events (SAEs)(Up to 6 months after the last 225Ac-PSMA-R2 dose administration)
- Dose Expansion: Incidence and severity of AEs and serious adverse events (SAEs)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Frequency of dose interruptions, reductions, discontinuations, and dose intensity by treatment.(At day 1 of each cycle (1 cycle = up to 6 weeks))
- Dose Escalation: Overall Response Rate (ORR)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Disease Control Rate (DCR)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Best Overall Response (BOR)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: radiographic Progression Free Survival (rPFS)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Overall Survival (OS)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Duration of Response (DoR)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Time to first Symptomatic Skeletal Event (SSE)(Assessed up to approximately 15 months.)
- Dose Escalation & Dose Expansion: Percentage of Participants with Biochemical Response by ALP and LDH(Assessed up to approximately 15 months.)
- Dose Escalation and Dose Expansion: Percentage of Participants with Biochemical Response by PSA(Assessed up to approximately 15 months.)
- Dose Escalation and Dose Expansion: Pharmacokinetics characterization of 225Ac-PSMA-R2(At Cycle (C) 1 Day (D) 1 at different measurement times, and one timepoint at C1 D2, C1 D3 and C1 D4)
- Dose escalation and dose expansion: To assess the impact of 225Ac-PSMA-R2 on participant reported outcomes(From baseline until 24 months after the end of treatment)
- Phase I Dose Escalation: Incidence and severity of AEs and serious adverse events (SAEs)(Up to 6 months after the last 225Ac-PSMA-R2 dose administration)
- Phase ll: Dose Expansion: Incidence and severity of AEs and serious adverse events (SAEs)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Dose Expansion: Frequency of dose interruptions, reductions, discontinuations, and dose intensity by treatment.(At day 1 of each cycle (1 cycle = up to 6 weeks))
- Phase I Dose Escalation: Overall Response Rate (ORR)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: Disease Control Rate (DCR)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: Best Overall Response (BOR)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: radiographic Progression Free Survival (rPFS)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: Overall Survival (OS)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: Duration of Response (DoR)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: Time to first Symptomatic Skeletal Event (SSE)(Assessed up to approximately 15 months.)
- Phase I Dose Escalation & Phase II Dose Expansion: Percentage of Participants with Biochemical Response by ALP and LDH(Assessed up to approximately 15 months.)
- Phase I Dose Escalation and Phase II Dose Expansion: Percentage of Participants with Biochemical Response by PSA(Assessed up to approximately 15 months.)
- Phase I Dose Escalation and Phase II: Dose Expansion: Pharmacokinetics characterization of 225Ac-PSMA-R2(At Cycle (C) 1 Day (D) 1 at different measurement times, and one timepoint at C1 D2, C1 D3 and C1 D4)
- Phase I Dose Escalation and Phase II Dose Expansion: To assess the impact of 225Ac-PSMA-R2 on participant reported outcomes(From baseline until 24 months after the end of treatment)